A dual role for hypoxia inducible factor-1α in the hepatitis C virus lifecycle and hepatoma migration

Abstract

Background & AimsHepatitis C virus (HCV) causes progressive liver disease and is a major risk factor for the development of hepatocellular carcinoma (HCC). However, the role of infection in HCC pathogenesis is poorly understood. We investigated the effect(s) of HCV infection and viral glycoprotein expression on hepatoma biology to gain insights into the development of HCV associated HCC.MethodsWe assessed the effect(s) of HCV and viral glycoprotein expression on hepatoma polarity, migration and invasion.ResultsHCV glycoproteins perturb tight and adherens junction protein expression, and increase hepatoma migration and expression of epithelial to mesenchymal transition markers Snail and Twist via stabilizing hypoxia inducible factor-1α (HIF-1α). HIF-1α regulates many genes involved in tumor growth and metastasis, including vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β). Neutralization of both growth factors shows different roles for VEGF and TGFβ in regulating hepatoma polarity and migration, respectively. Importantly, we confirmed these observations in virus infected hepatoma and primary human hepatocytes. Inhibition of HIF-1α reversed the effect(s) of infection and glycoprotein expression on hepatoma permeability and migration and significantly reduced HCV replication, demonstrating a dual role for HIF-1α in the cellular processes that are deregulated in many human cancers and in the viral life cycle.ConclusionsThese data provide new insights into the cancer-promoting effects of HCV infection on HCC migration and offer new approaches for treatment.

Low Oxygen Tension Enhances Hepatitis C Virus Replication

“…4A), HRE activity (see Fig. S2 in the supplemental material) was similar between HCV-and noninfected cells at early hours p.i., whereas at 72 h p.i., an ϳ2-fold increase was detected in infected cells, in agreement with studies (42)(43)(44) showing HIF-1 activation at late stages of HCV infection.…”

“…S6 in the supplemental material). Notably, HIF-1␣ activation from HCV at late stages of viral infection has been reported under normoxia and has been linked to mitochondrial dysfunction and oxidative stress caused by HCV proteins (42)(43)(44). In agreement with these studies, we also detected an increase in HIF-1␣ activation, but only 72 h p.i.…”

“…However, HIF-1␣ activation under normoxia is a general phenomenon in infection with bacteria, protozoa, and pathogenic viruses (29). HCV induces HIF-1␣ stabilization at late time points postinfection (42)(43)(44). Thus, we examined if the induction of HCV replication, observed at 3% O 2 , was related to HIF activation.…”

Hepatitis C Virus Induces Epithelial-Mesenchymal Transition in Primary Human Hepatocytes

“…Further study is necessary to verify the transition from EMT to an immortalized or transformed phenotype. A different report (42) suggested that the E-cadherin level is reduced in HCV glycoprotein-expressing HepG2 cells, and HCV infection promotes snail and twist expression in both Huh7.5 cells and primary human hepatocytes. However, those authors failed to observe any morphological fibroblast features of HCV-infected or glycoprotein-expressing hepatoma cells, possibly due to the partial de-differentiation process in vitro.…”

Differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono and co-infection identified by transcriptome profiling of PBMCs

“…Notable was the upregulation of HIF-α (EPAS1 and HIF1A), which led to the up-regulation of growth factors (TGFB2, TGFB3, VEGFA, PDGFB) and glucose transporter SLC2A1/GLUT1. Previous studies have shown that the expression of HCV protein activates HIF-1 by normoxic stabilization of its α subunit (HIF-α), resulting in increased expression of HIFcontrolled genes, many of which are involved in tumor growth and metastasis, such as VEGF and TGF-β [53][54][55].…”